Patterns of Variation and Linkage Disequilibrium in Key Pharmaceutical Genes Krishnan Nandabalan, Ph.D., J. Claiborne Stephens, Ph.D., Andreas Windemuth, Ph.D. Chuanbo Xu, Ph.D., Richard Judson, Ph.D., Jerry Vovis, Ph.D., Gualberto Ruano, M.D., Ph.D. Abstract One primary goal of the Human Genome Project is the identification of genes that play a role in medically relevant phenotypes. Although such genes can exert their influence when mutated, a more immediate challenge is the identification of functionally relevant polymorphisms, in that the latter are more likely to be widespread. In particular, genes involved in pharmacologically relevant pathways harbor many polymorphisms in their coding regions, their intron-exon boundaries, and their 5’ and 3’ regulatory regions. The utility of such polymorphisms is not only in their potential functional relevance, but also in their use as markers for discovering additional functional variants and for the general evaluation of a specific gene in the context of a given clinical phenotype. Utilization of markers in this capacity is greatly enhanced when knowledge of the local patterns of molecular evolution and linkage disequilibrium can be brought to bear on the evaluation of candidate loci. We have currently discovered variation in well over 1000 genes of pharmaceutical relevance. The emerging patterns of distribution for these variants, both within the genome and across human populations, will be discussed.
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